Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Differing levels of testosterone and the prostate: a physiological interplay

Nature Reviews Urology volume 8, pages 365–377 (2011)Cite this article

Subjects

Abstract

Abstract | The controversies surrounding testosterone replacement therapy (TRT) have been addressed in the past few years. Although the androgenic effects of TRT on normal and malignant prostate cells have been studied for over 70 years, little clinical prospective research exists on the physiological responses of prostate tissues to a wide range of serum testosterone levels. The prostate is both an androgen-dependent and an androgen-sensitive organ; active processes are triggered at a 'threshold' or 'saturation' level of testosterone. Despite decades of research, no compelling evidence exists that increasing testosterone beyond this threshold level has a causative role in prostate cancer, or indeed changes the biology of the prostate. Testosterone deficiency has marked physiological and clinical effects on men in middle age and beyond. With subnormal testosterone levels, the potential positive benefits of TRT on factors such as muscle mass, libido or erectile function are likely a dose–response phenomenon, and should be considered differently than the threshold influence on the prostate. This Review will re-examine classic androgen research and reflect on whether testosterone actually stimulates prostatic cellular growth and progression in a 'threshold' or a 'dose–response' (or both) manner, as well as discuss the influence of testosterone on prostate cells in the hypogonadal and eugonadal states.

Key Points

  • The risks and benefits of testosterone replacement therapy (TRT) need to be considered through the physiological mechanisms of proliferation, differentiation, and apoptosis studied in in vivo experiments over the past 70 years

  • The etiology of prostate cancer reflects a complex interplay between the domains of genetic determinants, endocrine milieu and environmental exposure—anecdotal cases of cancer in men on TRT demonstrate association, not causation

  • Multiple studies all conclude that testosterone level does not correlate with prostate cancer incidence; low (not absent) testosterone levels may actually be a marker of more-aggressive prostate cancer

  • It is likely that occult cancers or premalignant cells in hypogonadal men have adequate testosterone levels for healthy homeostasis and TRT does not provide any additional stimulus to growth

  • Maintaining a normal testosterone level throughout life may be beneficial from a survival point of view

  • To determine whether TRT increases de novo tumors, an appropriately powered prospective study would require 10,000 men randomized for 13 years, questions remain as to whether this type of study would be feasible

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Response of rat prostate to 5α-dihydrotestosterone administration.
Figure 2: Basic homeostatic responses of a hormone-sensitive organ.
Figure 3: Relationship between nuclear and cytoplasmic molar concentrations of dihydrotestosterone in rat prostate.

Similar content being viewed by others

References

  1. Wang, C. et al. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. Int. J. Impot. Res. 21, 1–8 (2009).

    Article  PubMed  Google Scholar 

  2. Harman, S. M., Metter, E. J., Tobin, J. D., Pearson, J. & Blackman, M. R. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 86, 724–731 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Araujo, A. B. et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J. Clin. Endocrinol. Metab. 89, 5920–5926 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Wu, F. C. et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J. Clin. Endocrinol. Metab. 93, 2737–2745 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Gooren, L. J., Behre, H. M., Saad, F., Frank, A. & Schwerdt, S. Diagnosing and treating testosterone deficiency in different parts of the world. Results from global market research. Aging Male 10, 173–181 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Huggins, C. & Hodges, C. V. Studies on prostatic cancer I: the effect of castration, of estrogen and of androgen injection on serum phospatases in metastatic carcinoma of the prostate. Cancer Res. 19, 293–297 (1941).

    Google Scholar 

  7. Huggins, C., Stevens, R. E. & Hodges, C. V. Studies on prostatic cancer II: the effects of castration on advanced carcinoma of the prostate gland. Arch. Surg. 43, 209–223 (1941).

    Article  CAS  Google Scholar 

  8. Bhasin, S. et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 95, 2536–2559 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Chute, R. & Willetts, A. T. The treatment of cancer of the prosate with castration and the administration of estrogen. N. Engl. J. Med. 227, 863–869 (1942).

    Article  Google Scholar 

  10. Moore, C. R., Hughes, W. & Gallagher, T. F. Rat seminal-vesicle cytology as a testis-hormone indicator and the prevention of castration changes by the testis-extract injection. Am. J. Anat. 45, 109–131 (1930).

    Article  CAS  Google Scholar 

  11. Moore, C. R., Price, D. & Gallagher, T. F. Rat-prostate cytology as a testis-hormone indicator and the prevention of castration changes by testis-extract injections. Am. J. Anat. 45, 71–107 (1930).

    Article  CAS  Google Scholar 

  12. Burkhart, E. Z. A study of the early effects of androgenic substances in the rat by the aid of colchicine. J. Exp. Zool. 89, 135–165 (1942).

    Article  CAS  Google Scholar 

  13. Huggins, C. Endocrine-induced regression of cancers. Cancer Res. 27, 1925–1930 (1967).

    CAS  PubMed  Google Scholar 

  14. Sheppard, H., Tsien, W. H., Mayer, P. & Howie, N. Metabolism of the accessory sex organs of the immature male rat: changes in nucleic acid composition and uptake of thymidine-3H induced by castration and methandrostenolone. Biochem. Pharmacol. 14, 41–51 (1965).

    Article  CAS  PubMed  Google Scholar 

  15. Coffey, D. S., Shimazaki, J. & Williams-Ashman, H. G. Polymerization of deoxyribonucleotides in relation to androgen-induced prostatic growth. Arch. Biochem. Biophys. 124, 184–198 (1968).

    Article  CAS  PubMed  Google Scholar 

  16. Lesser, B. & Bruchovsky, N. The effects of testosterone, 5-dihydrotestosterone and adenosine 3′, 5′-monophosphate on cell proliferation and differentiation in rat prostate. Biochim. Biophys. Acta 308, 426–437 (1973).

    Article  CAS  PubMed  Google Scholar 

  17. Lesser, B. & Bruchovsky, N. Effect of duration of the period after castration on the response of the rat ventral prostate to androgens. Biochem. J. 142, 429–431 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bruchovsky, N., Lesser, B., Van Doorn, E. & Craven, S. Hormonal effects on cell proliferation in rat prostate. Vitam. Horm. 33, 61–102 (1975).

    Article  CAS  PubMed  Google Scholar 

  19. Wright, A. S., Douglas, R. C., Thomas, L. N., Lazier, C. B. & Rittmaster, R. S. Androgen-induced regrowth in the castrated rat ventral prostate: role of 5α-reductase. Endocrinology 140, 4509–4515 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Rittmaster, R. S., Magor, K. E., Manning, A. P., Norman, R. W. & Lazier, C. B. Differential effect of 5α-reductase inhibition and castration on androgen-regulated gene expression in rat prostate. Mol. Endocrinol. 5, 1023–1029 (1991).

    Article  CAS  PubMed  Google Scholar 

  21. Fowler, J. E. Jr & Whitmore, W. F. Jr The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J. Urol. 126, 372–375 (1981).

    Article  PubMed  Google Scholar 

  22. Morgentaler, A. & Traish, A. M. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur. Urol. 55, 310–320 (2009).

    Article  PubMed  Google Scholar 

  23. Morgentaler, A., Lipshultz, L. I., Bennett, R., Sweeney, M., Avila, D. & Khera, M. Testosterone therapy in men with untreated prostate cancer. J. Urol. 195, 1256–1261 (2011).

    Article  CAS  Google Scholar 

  24. Khera, M. Androgen replacement therapy after cancer treatment. Curr. Urol. Rep. 11, 393–399 (2010).

    Google Scholar 

  25. Bosland, M. C. The role of steroid hormones in prostate carcinogenesis. J. Natl Cancer Inst. Monogr. 39–66 (2000).

  26. Morgentaler, A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur. Urol. 50, 935–939 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Banach-Petrosky, W. et al. Prolonged exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1; Pten mutant mice. Cancer Res. 67, 9089–9096 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Roddam, A. W., Allen, N. E., Appleby, P. & Key, T. J. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J. Natl Cancer Inst. 100, 170–183 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Stattin, P. et al. High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. Int. J. Cancer 108, 418–424 (2004).

    CAS  Google Scholar 

  30. Raynaud, J. P. Prostate cancer risk in testosterone-treated men. J. Steroid Biochem. Mol. Biol. 102, 261–266 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Sher, D. J. et al. Absence of relationship between steroid hormone levels and prostate cancer tumor grade. Urology 73, 356–361; discussion 361–352 (2009).

    Article  PubMed  Google Scholar 

  32. Severi, G. et al. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 15, 86–91 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Salonia, A. et al. Preoperative hypogonadism is not an independent predictor of high-risk disease in patients undergoing radical prostatectomy. Cancer doi:10.1002/cncr.25985 (2011).

  34. Imamoto, T. et al. Pretreatment serum testosterone level as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy. Eur. Urol. 47, 308–312 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Isom-Batz, G. et al. Testosterone as a predictor of pathological stage in clinically localized prostate cancer. J. Urol. 173, 1935–1937 (2005).

    Article  CAS  Google Scholar 

  36. Massengill, J. C. et al. Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. J. Urol. 169, 1670–1675 (2003).

    Article  PubMed  Google Scholar 

  37. Morgentaler, A. Testosterone deficiency and prostate cancer: emerging recognition of an important and troubling relationship. Eur. Urol. 52, 623–625 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Imamoto, T. et al. Does presence of prostate cancer affect serum testosterone levels in clinically localized prostate cancer patients? Prostate Cancer Prostatic Dis. 12, 78–82 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Hsing, A. W. Hormones and prostate cancer: what's next? Epidemiol. Rev. 23, 42–58 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Gann, P. H., Hennekens, C. H., Ma, J., Longcope, C. & Stampfer, M. J. Prospective study of sex hormone levels and risk of prostate cancer. J. Natl Cancer Inst. 88, 1118–1126 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Rhoden, E. L. & Morgentaler, A. Risks of testosterone-replacement therapy and recommendations for monitoring. N. Engl. J. Med. 350, 482–492 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Pierorazio, P. M. et al. Serum testosterone is associated with aggressive prostate cancer in older men: results from the Baltimore Longitudinal Study of Aging. BJU Int. 105, 824–829 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Heracek, J. et al. Tissue and serum levels of principal androgens in benign prostatic hyperplasia and prostate cancer. Steroids 72, 375–380 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Marks, L. S. et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA 296, 2351–2361 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Edwards, A., Hammond, H. A., Jin, L., Caskey, C. T. & Chakraborty, R. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics 12, 241–253 (1992).

    Article  CAS  PubMed  Google Scholar 

  46. Chang, C. S., Kokontis, J. & Liao, S. T. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 240, 324–326 (1988).

    Article  CAS  PubMed  Google Scholar 

  47. Chamberlain, N. L., Driver, E. D. & Miesfeld, R. L. The length and location of CAG trinucleotide repeats in the androgen receptor N.-terminal domain affect transactivation function. Nucleic Acids Res. 22, 3181–3186 (1994).

    Article  CAS  PubMed  Google Scholar 

  48. Giovannucci, E. et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc. Natl Acad. Sci. USA 94, 3320–3323 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Stanford, J. L. et al. Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res. 57, 1194–1198 (1997).

    CAS  PubMed  Google Scholar 

  50. Moilanen, A. M. et al. Characterization of androgen-regulated expression of CYP3A5 in human prostate. Carcinogenesis 28, 916–921 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Gao, J., Arnold, J. T. & Isaacs, J. T. Conversion from a paracrine to an autocrine mechanism of androgen-stimulated growth during malignant transformation of prostatic epithelial cells. Cancer Res. 61, 5038–5044 (2001).

    CAS  PubMed  Google Scholar 

  52. Chan, J. M. et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279, 563–566 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Damon, S. E., Maddison, L., Ware, J. L. & Plymate, S. R. Overexpression of an inhibitory insulin-like growth factor binding protein (IGFBP), IGFBP-4, delays onset of prostate tumor formation. Endocrinology 139, 3456–3464 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Munzer, T. et al. Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men. Am. J. Physiol. Endocrinol. Metab. 290, E1006–E1013 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Peng, L., Malloy, P. J., Wang, J. & Feldman, D. Growth inhibitory concentrations of androgens up-regulate insulin-like growth factor binding protein-3 expression via an androgen response element in LNCaP human prostate cancer cells. Endocrinology 147, 4599–4607 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Cohen, P. et al. Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J. Clin. Endocrinol. Metab. 75, 1046–1053 (1992).

    CAS  PubMed  Google Scholar 

  57. Risbridger, G. P., Bianco, J. J., Ellem, S. J. & McPherson, S. J. Oestrogens and prostate cancer. Endocr. Relat. Cancer 10, 187–191 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Giovannucci, E., Rimm, E. B., Stampfer, M. J., Colditz, G. A. & Willett, W. C. Diabetes mellitus and risk of prostate cancer (United States). Cancer Causes Control 9, 3–9 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Weiderpass, E., Ye, W., Vainio, H., Kaaks, R. & Adami, H. O. Reduced risk of prostate cancer among patients with diabetes mellitus. Int. J. Cancer 102, 258–261 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Stattin, P. et al. Leptin is associated with increased prostate cancer risk: a nested case-referent study. J. Clin. Endocrinol. Metab. 86, 1341–1345 (2001).

    CAS  PubMed  Google Scholar 

  61. Bubley, G. J. Is the flare phenomenon clinically significant? Urology 58, 5–9 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Freedland, S. J. & Partin, A. W. Prostate-specific antigen: update. Urology 67, 458–460 (2006) (2006).

    Article  PubMed  Google Scholar 

  63. Tomera, K. et al. The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. J. Urol. 165, 1585–1589 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Kuhn, J. M. et al. Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N. Engl. J. Med. 321, 413–418 (1989).

    Article  CAS  PubMed  Google Scholar 

  65. Bruchovsky, N., Klotz, L., Crook, J. & Goldenberg, S. L. Locally advanced prostate cancer--biochemical results from a prospective phase II study of intermittent androgen suppression for men with evidence of prostate-specific antigen recurrence after radiotherapy. Cancer 109, 858–867 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Buchan, N. C. & Goldenberg, S. L. Intermittent androgen suppression for prostate cancer. Nat. Rev. Urol. 7, 552–560 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Bhasin, S. et al. Testosterone dose-response relationships in healthy young men. Am. J. Physiol. Endocrinol. Metab. 281, E1172–E1181 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Cooper, C. S. et al. Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men. J. Urol. 159, 441–443 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Gould, D. C., Feneley, M. R. & Kirby, R. S. Prostate-specific antigen testing in hypogonadism: implications for the safety of testosterone-replacement therapy. BJU Int. 98, 1–4 (2006).

    Article  PubMed  Google Scholar 

  70. Behre, H. M., Bohmeyer, J. & Nieschlag, E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin. Endocrinol. (Oxf.) 40, 341–349 (1994).

    Article  CAS  Google Scholar 

  71. Swerdloff, R. S. & Wang, C. Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel. Aging Male 6, 207–211 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Roberts, J. T. & Essenhigh, D. M. Adenocarcinoma of prostate in 40-year-old body-builder. Lancet 328, 742 (1986).

    Article  Google Scholar 

  73. Guinan, P. D. et al. Impotence therapy and cancer of the prostate. Am. J. Surg. 131, 599–600 (1976).

    Article  CAS  PubMed  Google Scholar 

  74. Jackson, J. A., Waxman, J. & Spiekerman, A. M. Prostatic complications of testosterone replacement therapy. Arch. Intern. Med. 149, 2365–2366 (1989).

    Article  CAS  PubMed  Google Scholar 

  75. Loughlin, K. R. & Richie, J. P. Prostate cancer after exogenous testosterone treatment for impotence. J. Urol. 157, 1845 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Curran, M. J. & Bihrle, W. 3rd. Dramatic rise in prostate-specific antigen after androgen replacement in a hypogonadal man with occult adenocarcinoma of the prostate. Urology 53, 423–424 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Gaylis, F. D. et al. Prostate cancer in men using testosterone supplementation. J. Urol. 174, 534–538; discussion 538 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Bassil, N., Alkaade, S. & Morley, J. E. The benefits and risks of testosterone replacement therapy: a review. Ther. Clin. Risk Manag. 5, 427–448 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Gould, D. C. & Kirby, R. S. Testosterone replacement therapy for late onset hypogonadism: what is the risk of inducing prostate cancer? Prostate Cancer Prostatic Dis. 9, 14–18 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Kirby, R. & Gould, D. Testosterone replacement therapy in hypogonadal men and prostate cancer risk. BJU Int. 96, 471–472 (2005).

    Article  PubMed  Google Scholar 

  81. Bhasin, S. et al. Managing the risks of prostate disease during testosterone replacement therapy in older men: recommendations for a standardized monitoring plan. J. Androl. 24, 299–311 (2003).

    Article  PubMed  Google Scholar 

  82. Barqawi, A. B. & Crawford, E. D. Testosterone replacement therapy and the risk of prostate cancer: a perspective view. Int. J. Impot. Res. 17, 462–463 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Barqawi, A. & Crawford, E. D. Testosterone replacement therapy and the risk of prostate cancer. Is there a link? Int. J. Impot. Res. 18, 323–328 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Stanworth, R. D. & Jones, T. H. Testosterone for the aging male; current evidence and recommended practice. Clin. Interv. Aging 3, 25–44 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rhoden, E. L. & Averbeck, M. A. Testosterone therapy and prostate carcinoma. Curr. Urol. Rep. 10, 453–459 (2009).

    Article  PubMed  Google Scholar 

  86. Hajjar, R. R., Kaiser, F. E. & Morley, J. E. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J. Clin. Endocrinol. Metab. 82, 3793–3796 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Shabsigh, R., Crawford, E. D., Nehra, A. & Slawin, K. M. Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review. Int. J. Impot. Res. 21, 9–23 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Tenover, J. S. Effects of testosterone supplementation in the aging male. J. Clin. Endocrinol. Metab. 75, 1092–1098 (1992).

    CAS  PubMed  Google Scholar 

  89. Dobs, A. S. et al. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J. Clin. Endocrinol. Metab. 84, 3469–3478 (1999).

    CAS  PubMed  Google Scholar 

  90. Wang, C. et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J. Clin. Endocrinol. Metab. 89, 2085–2098 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Wang, C. et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J. Clin. Endocrinol. Metab. 85, 2839–2853 (2000).

    CAS  PubMed  Google Scholar 

  92. Sih, R. et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J. Clin. Endocrinol. Metab. 82, 1661–1667 (1997).

    Article  CAS  PubMed  Google Scholar 

  93. Guay, A. T., Perez, J. B., Fitaihi, W. A. & Vereb, M. Testosterone treatment in hypogonadal men: prostate-specific antigen level and risk of prostate cancer. Endocr. Pract. 6, 132–138 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Svetec, D. A., Canby, E. D., Thompson, I. M. & Sabanegh, E. S. Jr. The effect of parenteral testosterone replacement on prostate specific antigen in hypogonadal men with erectile dysfunction. J. Urol. 158, 1775–1777 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Kenny, A. M., Prestwood, K. M., Gruman, C. A., Marcello, K. M. & Raisz, L. G. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J. Gerontol. A Biol. Sci. Med. Sci. 56, M266–M272 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Gooren, L. J. A ten-year safety study of the oral androgen testosterone undecanoate. J. Androl. 15, 212–215 (1994).

    CAS  PubMed  Google Scholar 

  97. Gerstenbluth, R. E., Maniam, P. N., Corty, E. W. & Seftel, A. D. Prostate-specific antigen changes in hypogonadal men treated with testosterone replacement. J. Androl. 23, 922–926 (2002).

    PubMed  Google Scholar 

  98. Snyder, P. J. et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J. Clin. Endocrinol. Metab. 84, 1966–1972 (1999).

    CAS  PubMed  Google Scholar 

  99. Schubert, M. et al. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J. Clin. Endocrinol. Metab. 89, 5429–5434 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Feneley, M. R. & Carruthers, M. PSA monitoring during testosterone replacement therapy: low long-term risk of prostate cancer with improved opportunity for cure. Andrologia 36, 212 (2004).

    Google Scholar 

  101. Rhoden, E. L. & Morgentaler, A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J. Urol. 170, 2348–2351 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Snyder, P. J. et al. Effects of testosterone replacement in hypogonadal men. J. Clin. Endocrinol. Metab. 85, 2670–2677 (2000).

    CAS  PubMed  Google Scholar 

  103. Calof, O. M. et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J. Gerontol. A Biol. Sci. Med. Sci. 60, 1451–1457 (2005).

    Article  PubMed  Google Scholar 

  104. Lefkowitz, G. K., Taneja, S. S., Brown, J., Melamed, J. & Lepor, H. Followup interval prostate biopsy 3 years after diagnosis of high grade prostatic intraepithelial neoplasia is associated with high likelihood of prostate cancer, independent of change in prostate specific antigen levels. J. Urol. 168, 1415–1418 (2002).

    Article  PubMed  Google Scholar 

  105. Haggman, M. J., Macoska, J. A., Wojno, K. J. & Oesterling, J. E. The relationship between prostatic intraepithelial neoplasia and prostate cancer: critical issues. J. Urol. 158, 12–22 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Nesbit, R. M. & Baum, W. C. Endocrine control of prostatic carcinoma; clinical and statistical survey of 1, 818 cases. J. Am. Med. Assoc. 143, 1317–1320 (1950).

    Article  CAS  PubMed  Google Scholar 

  107. Brendler, H., Chase, W. E. & Scott, W. W. Prostatic cancer; further investigation of hormonal relationships. Arch. Surg. 61, 433–440 (1950).

    Article  CAS  PubMed  Google Scholar 

  108. Prout, G. R. Jr & Brewer, W. R. Response of men with advanced prostatic carcinoma to exogenous administration of testosterone. Cancer 20, 1871–1878 (1967).

    Article  PubMed  Google Scholar 

  109. Pearson, O. H. Discussion of Dr. Huggins' paper: Control of cancers of man by endocrinological methods. Cancer Res. 17, 473–479 (1957).

    CAS  PubMed  Google Scholar 

  110. Rawson, R. W. Hormonal control of neoplastic growth. Bull. N. Y. Acad. Med. 29, 595–611 (1953).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kaufman, J. M. & Graydon, R. J. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J. Urol. 172, 920–922 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Agarwal, P. K. & Oefelein, M. G. Testosterone replacement therapy after primary treatment for prostate cancer. J. Urol. 173, 533–536 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Sarosdy, M. F. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer 109, 536–541 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Khera, M. et al. Testosterone replacement therapy following radical prostatectomy. J. Sex. Med. 6, 1165–1170 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Rhoden, E. L., Averbeck, M. A. & Teloken, P. E. Androgen replacement in men undergoing treatment for prostate cancer. J. Sex. Med. 5, 2202–2208 (2008).

    Article  PubMed  Google Scholar 

  116. Zitzmann, M., Faber, S. & Nieschlag, E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J. Clin. Endocrinol. Metab. 91, 4335–4343 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Wu, F. C. et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N. Engl. J. Med. 363, 123–135 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Stanworth, R. D., Kapoor, D., Channer, K. S. & Jones, T. H. Androgen receptor CAG repeat polymorphism is associated with serum testosterone levels, obesity and serum leptin in men with type 2 diabetes. Eur. J. Endocrinol. 159, 739–746 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Shores, M. M., Matsumoto, A. M., Sloan, K. L. & Kivlahan, D. R. Low serum testosterone and mortality in male veterans. Arch. Intern. Med. 166, 1660–1665 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Laughlin, G. A., Barrett-Connor, E. & Bergstrom, J. Low serum testosterone and mortality in older men. J. Clin. Endocrinol. Metab. 93, 68–75 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. [No listed authors] Medication Guides. FDA [online], (2011).

  122. Malkin, C. J. et al. Low serum testosterone and increased mortality in men with coronary heart disease. Heart 96, 1821–1825 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Basaria, S. et al. Adverse events associated with testosterone administration. N. Engl. J. Med. 363, 109–122 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urologic Sciences, Department of Urologic Sciences, University of British Columbia, Level 6, 2775 Laurel Street, Vancouver, V5Z 1M9, BC, Canada

    S. Larry Goldenberg, Anthony Koupparis & Michael E. Robinson

Authors
  1. S. Larry Goldenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony Koupparis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael E. Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S. L. Goldenberg, A. Koupparis and M. E. Robinson contributed equally to researching, discussing, writing, reviewing and editing this article.

Corresponding author

Correspondence to S. Larry Goldenberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goldenberg, S., Koupparis, A. & Robinson, M. Differing levels of testosterone and the prostate: a physiological interplay. Nat Rev Urol 8, 365–377 (2011). https://doi.org/10.1038/nrurol.2011.79

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2011.79

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing